GÉRARD FRIEDLANDER

This project, which combines experimental and clinical research, takes place in the context of the renewal of the “Growth and Signaling” Inserm Research Center U845 on the Necker campus.

Phosphate homeostasis

Phosphate (Pi) homeostasis has a central place in metabolism, cellular proliferation, development, and bone mineralization. Pi homeostasis relies on a coordinate function of membrane transporters (ubiquitous PiT, epithelial NPT), of intracellular regulatory proteins and of endocrine and paracrine modulators. Our goal is to study Pi homeostasis at the cellular level and in the whole organism, both in normal and pathological situations.

Cellular Pi homeostasis

Cellular and molecular Pi physiology

We propose (a) to investigate the specificity of PiT1 and PiT2 expression in response to transcription factors and growth factors through promoter studies; (b) to get insights into the mechanisms underlying the role of PiT1 in cell proliferation and modulation of the cell cycle; (c) to evaluate the role of PiT1 and PiT2 as Pi sensors.

Consequences of PiT1 invalidation.

We shall evaluate, in vivo, the phenotypic consequences of PiT knockout (allelic series obtained by homologous recombination) or conditional invalidation (cre-lox) in the mouse: (a) during development, focusing on bone, liver and kidney; (b) in pathological situations (renal acute and chronic injury, liver regeneration and hepatocarcinoma.

Phosphate homeostasis at the organism level

This clinical research aims to (a) dissect at the molecular level renal Pi leaks which lead to renal stones and bone loss: identification and characterization (heterologous expression) of mutations affecting renal transporters NPT2a, NPT2c, and regulatory proteins NHERF1 and NHERF2; (b) look for structure/secretion abnormalities of phosphaturic peptides such as FGF23; evaluate the implication of klotho, a recently identified gene involved in cardiovascular aging, in end stage renal failure-associated hyperphosphatemia and in vitamin D metabolism.

Our group has been involved in the study of phosphate homeostasis and phosphate transporters for many years, mainly epithelial transporters of the kidney and the intestine. Five years ago, we turned to more widely expressed transporters, PiT1 and PiT2, also known as retrovirus receptors. The knockout of PiT1 revealed a phenotype associating embryonic death at E12.5, major anemia and defect in liver growth with massive apoptosis (Beck L et al. PLoS One 2009). We also demonstrated that PiT1 plays a key role in the control of proliferation and apoptosis of cancer cells (Beck L et al J Biol Chem 2009, Salaün et al J Biol Chem 2010). We are currently exploring the phenotype of mice bearing a hypomorphic mutation of PiT1 and expressing only 15% of the total amount of this transporter. These animals are anemic with defects in red blood cell structure and in their production and destruction.

This project, which combines experimental and clinical research, takes place in the context of the renewal of the “Growth and Signaling” Inserm Research Center U845 on the Necker campus.